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Aconitine is a crucial toxic component in Chinese herbal medicines such as Aconitum, Aconitum coreanum, and Aconitum soongaricum. The poisoning symptoms of the central nervous system and cardiovascular system caused by it are relatively common in China, and there are many studies on cardiovascular system diseases caused by aconitine. However, the specific mechanism of neurotoxicity induced by aconitine is still unclear. This study explored the effect and mechanism of mitochondrial calcium uniporter on mitochondrial energy metabolism disorder in aconitine poisoning hippocampal neurons. The results showed that after treatment with 400μmol/L aconitine, mitochondrial energy metabolism was abnormal in rat hippocampal neuron cells, the expression of MCU in mitochondria was up-regulated, calcium overload in mitochondria, ATP production decreased, and mitochondrial membrane potential Changes, increased expression of the apoptosis gene Cleaved-Caspase-3. After treatment with the MCU agonist spermine, mitochondrial energy metabolism was significantly abnormal, and cell apoptosis was increased considerably. However, pretreatment with calcium ion channel inhibitor Ruthenium Red (RR) effectively promoted the generation of ATP, thereby improving mitochondrial energy metabolism disorders and reducing cell apoptosis. These results suggest that aconitine induces mitochondrial energy metabolism dysfunction in hippocampal neurons, which may be related to the increased expression of MCU., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Haiying Wu reports financial support was provided by National Natural Science Foundation of China. Haiying Wu reports a relationship with National Natural Science Foundation of China that includes: funding grants., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aconitine, a highly toxic alkaloid derived from Aconitum L., affects the central nervous system and peripheral nervous system. However, the underlying mechanism of aconitine-induced neurotoxicity remains unclear. This study investigates the effects and mechanism of aconitine on mitochondrial energy metabolism in SH-SY5Y cells. Results demonstrated that aconitine exposure suppressed cell proliferation and led to an increase in reactive oxygen species (ROS) and excessive lactate dehydrogenase (LDH) release. Aconitine (400 μmol/L) induced abnormal mitochondrial energy metabolism that quantified by the significant decrease in ATP production, basal respiration, proton leak, maximal respiration, and succinate dehydrogenase (SDH) activity. Phosphorylation of AMPK was significantly reduced in aconitine-treated SH-SY5Y cells. The AMPK activator AIACR pretreatment effectively promoted ATP production to ameliorate mitochondrial energy metabolism disorder caused by aconitine. Mitochondrial biosynthesis was inhibited after treatment with 400 μmol/L aconitine, which was characterized by mitochondria number, TFAM expression, and mtDNA copy number. Moreover, aconitine prompted the down-regulation of mitochondrial fusion proteins OPA1, Mfn1 and Mfn2, and the up-regulation of mitochondrial fission proteins p-Drp1 and p-Mff. These results suggest that aconitine induces mitochondrial energy metabolism dysfunction in SH-SY5Y cells, which may involve the inhibition of AMPK signaling and abnormal mitochondrial dynamics., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aconitine (AC) and mesaconitine (MA) are major bioactive diterpenoid alkaloids derived from herbal aconitum plants. Emerging evidence indicates that AC plays a pivotal role in the cardiotoxicity for aconite poisoning. However, the cardiotoxicity data of MA, especially those on the difference between AC and MA are quite limited. Zebrafish embryos were used in this study for toxicological screening, and the cardiac morphology and function were observed. Embryos were analyzed by means of high-performance liquid chromatography (HPLC) after exposure and pharmacokinetic behaviors were also investigated. Results showed that 1.5% of the aconitum alkaloids penetrated into the zebrafish embryos. 2.5 μg/L AC and 20 μg/L MA caused a deficient cardiovascular system with yolk sac hemorrhage and early cardiac dysfunctions were observed in 96 h post-fertilization. AC showed greater cardiotoxicity than MA by comparing the EC 50 of pericardium edema. Aconitum alkaloids exposure also resulted in a significant decrease in the expression of cardiac genes (Tbx5, Gata4, and Nkx2.5) from an early stage (12-24 hpf), which may partly explained that the death caused by aconitum is most likely to occur within the first 24 h. In addition, a high percentage of apoptotic cells was observed in the brain region, which identified another potential target of the DDA action in zebrafish embryos., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aconitum alkaloids including aconitine (AC), mesaconitine (MA), hypaconitine (HA), are highly toxic. Their hydrolysates, such as benzoylaconine (BAC), benzoylmesaconine (BMA), benzoylhypaconine (BHA), aconine, and mesaconine, are considerably less toxic. Efflux transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein isoform 2 (MRP2), act as a first line of defence and play key roles in toxicity prevention. The aim of the present study was to determine the role of efflux transporters in the transport of Aconitum alkaloids using cultured Caco-2, MDR1-MDCKII and BCRP-MDCKII cells. Bidirectional transport assays of the Aconitum alkaloids were performed with or without P-gp (cyclosporine A and verapamil), BCRP (Ko143) and MRP2 (MK571) inhibitors. The efflux ratios (Er) of AC, MA, and HA in Caco-2 cells were 34.6±4.2, 29.7±2.1, and 15.6±2.1, respectively; those of BAC, BMA, and BHA were approximately 4, and those of aconine and mesaconine were equal to 1. The Er values of AC, MA, and HA in MDR1-MDCKII and BCRP-MDCKII cells were significantly higher than those in parental MDCKII cells. Taken together the results of Er values and intracellular amounts in the presence of inhibitors, P-gp and BCRP were involved in the transport of AC, MA and HA; and MRP2 might transport AC, MA, HA, BAC, BMA and BHA., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Aconitine (AC), a famous major Aconitum alkaloid, has effective antirheumatic function with high toxicity. The aim of our study was to in-depth investigate cytochrome P450 isozymes (CYPs) involved in aconitine metabolism in vitro. We used human liver microsomes (HLMs) as well as recombinant CYPs to investigate the metabolism pathways of aconitine by liquid chromatography-tandem mass spectrometry. Fluvoxamine maleate, gemfibrozil, amiodarone hydrochloride, omeprazole, quinidine, diethyldithiocarbamic acid and ketoconazole were successfully applied as test inhibitors for CYP1A2, CYP2C8, CYP2C9, CYP2C19*1, CYP2D6*1, CYP2E1 and CYP3A4/5 in HLMs, respectively. Six CYP-mediated metabolites were found and characterized in human liver microsomes and eight recombinant CYP isoforms. The inhibitor of CYP 3A had a strong inhibitory effect, the inhibitors of CYP 2C9, 2C8 and CYP2D6 had little inhibitory effects, whereas CYP2C19, 1A2 and 2E1 had no obvious inhibitory effects on AC metabolism. Hydroxylation and di-demethylation of aconitine were conducted by human recombinant CYP 3A5 and 2D6, dehydrogenation was only processed by CYP3A4/5, and the main CYP isoforms metabolizing aconitine to demethyl-aconitine and N-deethyl-aconitine were CYP3A4/5 and CYP2D6. In conclusion, aconitine can be transformed into at least six CYP-mediated metabolites in HLMs, CYP 3A4/5 and 2D6 were the most important CYP isoforms responsible for the de-methylation, N-deethylation, dehydrogenation, and hydroxylation of aconitine., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)